Nighttime color constancy using robust gray pixels.

Color constancy is a basic step for achieving stable color perception in both biological visual systems and the image signal processing (ISP) pipeline of cameras. So far, there have been numerous computational models of color constancy that focus on scenes under normal light conditions but are less concerned with nighttime scenes. Compared with daytime scenes, nighttime scenes usually suffer from relatively higher-level noise and insufficient lighting, which usually degrade the performance of color constancy methods designed for scenes under normal light. In addition, there is a lack of nighttime color constancy datasets, limiting the development of relevant methods. In this paper, based on the gray-pixel-based color constancy methods, we propose a robust gray pixel (RGP) detection method by carefully designing the computation of illuminant-invariant measures (IIMs) from a given color-biased nighttime image. In addition, to evaluate the proposed method, a new dataset that contains 513 nighttime images and corresponding ground-truth illuminants was collected. We believe this dataset is a useful supplement to the field of color constancy. Finally, experimental results show that the proposed method achieves superior performance to statistics-based methods. In addition, the proposed method was also compared with recent deep-learning methods for nighttime color constancy, and the results show the method's advantages in cross-validation among different datasets.

Advances in transcorneal electrical stimulation: From the eye to the brain.

The mammalian brain is reported to contain about 106-109 neurons linked together to form complex networks. Physiologically, the neuronal networks interact in a rhythmic oscillatory pattern to coordinate the brain's functions. Neuromodulation covers a broad range of techniques that can alter neuronal network activity through the targeted delivery of electrical or chemical stimuli. Neuromodulation can be used to potentially treat medical conditions and can serve as a research tool for studying neural functions. Typically, the main method of neuromodulation is to electrically stimulate specific structures in both the central and peripheral nervous systems via surgically implanted electrodes. Therefore, it is imperative to explore novel and safer methods for altering neuronal network activity. Transcorneal electrical stimulation (TES) has rapidly emerged as a non-invasive neuromodulatory technique that can exert beneficial effects on the brain through the eyes. There is substantial evidence to show that TES can change the brain oscillations in rodents. Moreover, the molecular data clearly shows that TES can also activate non-visual brain regions. In this review, we first summarize the use of TES in the retina and then discuss its effects in the brain through the eye-brain connection. We then comprehensively review the substantial evidence from electrophysiological, behavioral, and molecular studies on the role of TES on modulating neurons in the brain. Lastly, we discuss the implications and possible future directions of the research on TES as a non-invasive tool for neuromodulation of the brain via directly stimulating the mammalian eye.

Neuromodulation in the developing visual cortex after long-term monocular deprivation.

Neural dynamics are altered in the primary visual cortex (V1) during critical period monocular deprivation (MD). Synchronization of neural oscillations is pertinent to physiological functioning of the brain. Previous studies have reported chronic disruption of V1 functional properties such as ocular dominance, spatial acuity, and binocular matching after long-term monocular deprivation (LTMD). However, the possible neuromodulation and neural synchrony has been less explored. Here, we investigated the difference between juvenile and adult experience-dependent plasticity in mice from intracellular calcium signals with fluorescent indicators. We also studied alterations in local field potentials power bands and phase-amplitude coupling (PAC) of specific brain oscillations. Our results showed that LTMD in juveniles causes higher neuromodulatory changes as seen by high-intensity fluorescent signals from the non-deprived eye (NDE). Meanwhile, adult mice showed a greater response from the deprived eye (DE). LTMD in juvenile mice triggered alterations in the power of delta, theta, and gamma oscillations, followed by enhancement of delta-gamma PAC in the NDE. However, LTMD in adult mice caused alterations in the power of delta oscillations and enhancement of delta-gamma PAC in the DE. These markers are intrinsic to cortical neuronal processing during LTMD and apply to a wide range of nested oscillatory markers.

Neuronal Oscillatory Signatures in the Developing Mouse Visual Cortex After Short-Term Monocular Deprivation.

Development and maturation in cortical networks depend on neuronal activity. For stabilization and pruning of connections, synchronized oscillations play a crucial role. A fundamental mechanism that enables coordinated activity during brain functioning is formed of synchronized neuronal oscillations in low- (delta and theta) and high- (gamma) frequency bands. The relationship between neural synchrony, cognition, and the perceptual process has been widely studied, but any possible role of neural synchrony in amblyopia has been less explored. We hypothesized that monocular deprivation (MD) during early postnatal life would lead to changes in neuronal activity that would be demonstrated by changes in phase-amplitude coupling (PAC) and altered power in specific oscillatory frequency. Our results demonstrate that functional connectivity in the visual cortex is altered by MD during adolescence. The amplitude of high-frequency oscillations is modulated by the phase of low-frequency oscillations. Demonstration of enhanced delta-gamma and theta-gamma PAC indicates that our results are relevant for a broad range of nested oscillatory markers. These markers are inherent to neuronal processing and are consistent with the hypothesized increase in the intrinsic coupling that arises from neural oscillatory phase alignment. Our results reveal distinct frequency bands exhibit altered power and coherence variations modulated by experience-driven plasticity.

Transcorneal electrical stimulation enhances cognitive functions in aged and 5XFAD mouse models.

Dementia is a major burden on global health for which there are no effective treatments. The use of noninvasive visual stimulation to ameliorate cognitive deficits is a novel concept that may be applicable for treating dementia. In this study, we investigated the effects of transcorneal electrical stimulation (TES) on memory enhancement using two mouse models, in aged mice and in the 5XFAD model of Alzheimer's disease. After 3 weeks of TES treatment, mice were subjected to Y-maze and Morris water maze tests to assess hippocampal-dependent learning and memory. Immunostaining of the hippocampus of 5XFAD mice was also performed to examine the effects of TES on amyloid plaque pathology. The results showed that TES improved the performance of both aged and 5XFAD mice in memory tests. TES also reduced hippocampal plaque deposition in male, but not female, 5XFAD mice. Moreover, TES significantly reversed the downregulated level of postsynaptic protein 95 in the hippocampus of male 5XFAD mice, suggesting the effects of TES involve a postsynaptic mechanism. Overall, these findings support further investigation of TES as a potential treatment for cognitive dysfunction and mechanistic studies of TES effects in other dementia models.

Antidepressant-like effects of transcorneal electrical stimulation in rat models.

BACKGROUND: Given that visual impairment is bi-directionally associated with depression, we examined whether transcorneal electrical stimulation (TES), a non-invasive treatment for visual disorders, can ameliorate depressive symptoms. OBJECTIVE: The putative antidepressant-like effects of TES and the underlying mechanisms were investigated in an S334ter-line-3 rat model of retinal degeneration and a rat model of chronic unpredictable stress (CUS). METHODS: TES was administered daily for 1 week in S334ter-line-3 and CUS rats. The effects of TES on behavioral parameters, plasma corticosterone levels, and different aspects of neuroplasticity, including neurogenesis, synaptic plasticity, and apoptosis, were examined. RESULTS: In S334ter-line-3 rats, TES induced anxiolytic and antidepressant-like behaviors in the cylinder, open field, home cage emergence, and forced swim tests. In the CUS rat model, TES induced hedonic-like behavior and decreased behavioral despair, which were accompanied by reduced plasma corticosterone levels and upregulated expression of neurogenesis-related genes. Treatment with the neurogenesis blocker temozolomide only inhibited the hedonic-like effect of TES, suggesting the antidepressant-like effects of TES were mediated through both neurogenesis-dependent and -independent mechanisms. Furthermore, TES was found to normalize the protein expression of synaptic markers and apoptotic Bcl-2-associated X protein in the hippocampus and amygdala in the CUS rat model. The improvements in neuroplasticity may involve protein kinase B (AKT) and protein kinase A (PKA) signaling pathways in the hippocampus and amygdala, respectively, as demonstrated by the altered pAKT/AKT and pPKA/PKA ratios. CONCLUSION: The overall findings suggest a possible neuroplasticity mechanism of the antidepressant-like effects of TES.

Transcorneal Electrical Stimulation Induces Long-Lasting Enhancement of Brain Functional and Directional Connectivity in Retinal Degeneration Mice.

To investigate neuromodulation of functional and directional connectivity features in both visual and non-visual brain cortices after short-term and long-term retinal electrical stimulation in retinal degeneration mice. We performed spontaneous electrocorticography (ECoG) in retinal degeneration (rd) mice following prolonged transcorneal electrical stimulation (pTES) at varying currents (400, 500 and 600 µA) and different time points (transient or day 1 post-stimulation, 1-week post-stimulation and 2-weeks post-stimulation). We also set up a sham control group of rd mice which did not receive any electrical stimulation. Subsequently we analyzed alterations in cross-frequency coupling (CFC), coherence and directional connectivity of the primary visual cortex and the prefrontal cortex. It was observed that the sham control group did not display any significant changes in brain connectivity across all stages of electrical stimulation. For the stimulated groups, we observed that transient electrical stimulation of the retina did not significantly alter brain coherence and connectivity. However, for 1-week post-stimulation, we identified enhanced increase in theta-gamma CFC. Meanwhile, enhanced coherence and directional connectivity appeared predominantly in theta, alpha and beta oscillations. These alterations occurred in both visual and non-visual brain regions and were dependent on the current amplitude of stimulation. Interestingly, 2-weeks post-stimulation demonstrated long-lasting enhancement in network coherence and connectivity patterns at the level of cross-oscillatory interaction, functional connectivity and directional inter-regional communication between the primary visual cortex and prefrontal cortex. Application of electrical stimulation to the retina evidently neuromodulates brain coherence and connectivity of visual and non-visual cortices in retinal degeneration mice and the observed alterations are largely maintained. pTES holds strong possibility of modulating higher cortical functions including pathways of cognition, awareness, emotion and memory.

Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression.

Transcorneal electrical stimulation (TES) has emerged as a non-invasive neuromodulation approach that exerts neuroprotection via diverse mechanisms, including neurotrophic, neuroplastic, anti-inflammatory, anti-apoptotic, anti-glutamatergic, and vasodilation mechanisms. Although current studies of TES have mainly focused on its applications in ophthalmology, several lines of evidence point towards its putative use in treating depression. Apart from stimulating visual-related structures and promoting visual restoration, TES has also been shown to activate brain regions that are involved in mood alterations and can induce antidepressant-like behaviour in animals. The beneficial effects of TES in depression were further supported by its shared mechanisms with FDA-approved antidepressant treatments, including its neuroprotective properties against apoptosis and inflammation, and its ability to enhance the neurotrophic expression. This article critically reviews the current findings on the neuroprotective effects of TES and provides evidence to support our hypothesis that TES possesses antidepressant effects.

Monitoring Cortical Response and Electrode-Retina Impedance Under Epiretinal Stimulation in Rats.

Retinal prosthesis can restore partial vision in patients with retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration. Epiretinal prosthesis is one of three therapeutic approaches, which received regulatory approval several years ago. The thresholds of an epiretinal stimulation is partly determined by the size of the physical gap between the electrode and the retina after implantation. Precise positioning of epiretinal stimulating electrode array is still a challenging task. In this study, we demonstrate an approach to positioning epiretinal prostheses for an optimal response at the cortical output by monitoring both the impedance at the electrode-retina interface and the evoked-potential at the cortical level. We implanted a single-channel electrode on the epiretinal surface in adult rats, acutely, guided by both the impedance at the electrode-retina interface and by electrically evoked potentials (EEPs) in the visual cortex during retinal stimulation. We observe that impedance monotonously increases with decreasing electrode-retina distance, but that the strongest cortical responses were achieved at intermediate impedance levels. When the electrode penetrates the retina, the impedance keeps increasing. The effect of stimulation on the retina changes from epiretinal paradigm to intra-retinal paradigm and a decrease in cortical activation is observed. It is found that high impedance is not always favorable to elicit best cortical responses. Histopathological results showed that the electrode was placed at the intra-retinal space at high impedance value. These results show that monitoring impedance at the electrode-retina interface is necessary but not sufficient in obtaining strong evoked-potentials at the cortical level. Monitoring the cortical EEPs together with the impedance can improve the safety of implantation as well as efficacy of stimulation in the next generation of retinal implants.

Excitation of the Pre-frontal and Primary Visual Cortex in Response to Transcorneal Electrical Stimulation in Retinal Degeneration Mice.

Retinal degeneration (rd) is one of the leading causes of blindness in the modern world today. Various strategies including electrical stimulation are being researched for the restoration of partial or complete vision. Previous studies have demonstrated that the effectiveness of electrical stimulation in somatosensory, frontal and visual cortices is dependent on stimulation parameters including stimulation frequency and brain states. The aim of the study is to investigate the effect of applying a prolonged electrical stimulation on the eye of rd mice with various stimulation frequencies, in awake and anesthetized brain states. We recorded spontaneous electrocorticogram (ECoG) neural activity in prefrontal cortex and primary visual cortex in a mouse model of retinitis pigmentosa (RP) after prolonged (5-day) transcorneal electrical stimulation (pTES) at various frequencies (2, 10, and 20 Hz). We evaluated the absolute power and coherence of spontaneous ECoG neural activities in contralateral primary visual cortex (contra Vcx) and contralateral pre-frontal cortex (contra PFx). Under the awake state, the absolute power of theta, alpha and beta oscillations in contra Vcx, at 10 Hz stimulation, was higher than in the sham group. Under the anesthetized state, the absolute power of medium-, high-, and ultra-high gamma oscillations in the contra PFx, at 2 Hz stimulation, was higher than in the sham group. We also observed that the ultra-high gamma band coherence in contra Vcx-contra PFx was higher than in the sham group, with both 10 and 20 Hz stimulation frequencies. Our results showed that pTES modulates rd brain oscillations in a frequency and brain state-dependent manner. These findings suggest that non-invasive electrical stimulation of retina changes patterns of neural oscillations in the brain circuitry. This also provides a starting point for investigating the sustained effect of electrical stimulation of the retina to brain activities.

Residual contrast response in primary visual cortex of rats with inherited retinal degeneration.

Rhodopsin S334ter-3 retinal degeneration rats have been widely used to investigate degenerative diseases of the retina. In this model, morphological and electrophysiological changes have been observed in the retina, superior colliculus and primary visual cortex (V1). However, no study so far has examined rhodopsin S334ter-3 rats with regards to their contrast response in V1 - a fundamental property of visual information processing. In this study, experimental rats (S334ter-3) carried one copy of the mutant transgene. We compared responses to spatio-temporal variations in luminance contrast in the primary visual cortex of these rats with those in Long-Evans (LE) rats to elucidate the degeneration-specific activity changes in this part of the visual pathway. We measured extracellular responses to different stimulus contrasts at the preferred parameters of each recorded cell under classical receptive field (CRF) stimulation. Our results show that V1 cells in the S334ter-3 group exhibit stronger spontaneous activity but weaker stimulus-evoked responses at medium and high contrasts. By fitting responses to a sigmoid function, we found that the S334ter-3 group had a lower Rmax but a larger exponent N than the LE group. However, we did not find a significant difference in C50 value. These results indicate the decrease in discriminating the stimuli contrast and loss in responses and lower signal to noise ratio after retinal degeneration. Our study supports the notion that a considerable degree of plasticity is found in cortex after retinal degeneration, indicating that visual restoration therapies would succeed if the retina could send useful signals to the brain.

Penetrating the Blood-Brain Barrier by Self-Assembled 3D DNA Nanocages as Drug Delivery Vehicles for Brain Cancer Therapy.

The development of biocompatible drug delivery vehicles for cancer therapy in the brain remains a big challenge. In this study, we designed self-assembled DNA nanocages functionalized with or without blood-brain barrier (BBB)-targeting ligands, d and we investigated their penetration across the BBB. Our DNA nanocages were not cytotoxic and they were substantially taken up in brain capillary endothelial cells and Uppsala 87 malignant glioma (U-87 MG) cells. We found that ligand modification is not essential for this DNA system as the ligand-free DNA nanocages (LF-NCs) could still cross the BBB by endocytosis inin vitro and in vivo models. Our spherical DNA nanocages were more permeable across the BBB compared with tubular DNA nanotubes. Remarkably, in vivo studies revealed that DNA nanocages could carry anticancer drugs across the BBB and inhibit the tumor growth in a U-87 MG xenograft mouse model. This is the first example showing the potential of DNA nanocages as innovative delivery vehicles to the brain for cancer therapy. Unlike other delivery systems, our work suggest that a DNA nanocage-based platform provides a safe and cost-effective tool for targeted delivery to the brain and therapy for brain tumors.

Monocular Visual Deprivation and Ocular Dominance Plasticity Measurement in the Mouse Primary Visual Cortex.

Monocular visual deprivation is an excellent experimental paradigm to induce primary visual cortical response plasticity. In general, the response of the cortex to the contralateral eye to a stimulus is much stronger than the response of the ipsilateral eye in the binocular segment of the mouse primary visual cortex (V1). During the mammalian critical period, suturing the contralateral eye will result in a rapid loss of responsiveness of V1 cells to contralateral eye stimulation. With the continuing development of transgenic technologies, more and more studies are using transgenic mice as experimental models to examine the effects of specific genes on ocular dominance (OD) plasticity. In this study, we introduce detailed protocols for monocular visual deprivation and calculate the change in OD plasticity in mouse V1. After monocular deprivation (MD) for 4 days during the critical period, the orientation tuning curves of each neuron are measured, and the tuning curves of layer four neurons in V1 are compared between stimulation of the ipsilateral and contralateral eyes. The contralateral bias index (CBI) can be calculated using each cell's ocular OD score to indicate the degree of OD plasticity. This experimental technique is important for studying the neural mechanisms of OD plasticity during the critical period and for surveying the roles of specific genes in neural development. The major limitation is that the acute study cannot investigate the change in neural plasticity of the same mouse at a different time.

Responsive Neural Activities in the Primary Visual Cortex of Retina-Degenerated Rats.

To study the responsive neural activities in the primary visual cortex (V1) of retinal degeneration (RD) models, experiments involving the wild-type (WT) and RD rats were conducted. The neural responses in the V1 were recorded extracellularly, while a visual stimulus with varied light intensity was given to the subjects. First, the firing rate and its relationship with light intensity were compared between the WT and RD groups. Second, the mutual information (MI) between the visual stimulus and neural response was determined for every isolated unit to quantify the amount and efficiency of information transmission in the V1 for both the control and experimental groups. Third, the local field potential (LFP) signal was characterized and its power used to compute the MI and further evaluate the function change in the RD model regarding information transmission. Analysis of spiking activity showed that the RD group exhibited a relatively decreased firing rate, information amount and efficiency compared with the control group. However, the information transmission performance of the RD model was similar to that of the WT group in the context of LFP activity. Therefore, for the RD rats, the early stage of the visual system was impaired, while the later stage of the visual system, V1, was able to capture the information about the visual stimulus, especially at the population level. Thus, this pathway could be used to restore visual ability, such as by visual prostheses.

Temporal Neuromodulation of Retinal Ganglion Cells by Low-Frequency Focused Ultrasound Stimulation.

Significant progress has been made recently in treating neurological blindness using implantable visual prostheses. However, implantable medical devices are highly invasive and subject to many safety, efficacy, and cost issues. The discovery that ultrasound (US) may be useful as a noninvasive neuromodulation tool has aroused great interest in the field of acoustic retinal prostheses (ARPs). We have investigated the responsiveness of rat retinal ganglion cells (RGCs) to low-frequency focused US stimulation (LFUS) at 2.25 MHz and characterized the neurophysiological properties of US responses by performing in vitro multielectrode array recordings. The results show that LFUS can reliably activate RGCs. The US-induced responses did not correspond to the standard light responses and varied greatly among cell types. Moreover, dual-peak responses to US stimulation were observed that have not been reported previously. The temporal response properties of RGCs, including their latency, firing rate, and response type, were modulated by the acoustic intensity. These findings suggest the presence of a temporal neuromodulation effect of LFUS and potentially open a new avenue in the development of ARP.

Neural Probes with Integrated Temperature Sensors for Monitoring Retina and Brain Implantation and Stimulation.

Gold (Au) resistive temperature sensors were integrated on flexible polyimide-based neural probes to monitor temperature changes during neural probe implantation and stimulation. Temperature changes were measured as neural probes were implanted to infer the positions of the neural probes, and as the retina or the deep brain region was stimulated electrically. The temperature sensor consisted of a serpentine Au resistor and surrounded by four Au electrodes with 200 and [Formula: see text] diameter (dia.). The Au temperature sensors had temperature coefficient of 0.32%, and they were biocompatible and small in size. In vivo measurements of temperature changes during implantation and stimulation were carried out in the retina and deep brain region in rats. The desired implantation position was reached when temperature measured by the sensor increased to the calibrated level and became stable. There was no temperature increase when low level stimulation current of 8 and [Formula: see text] each for the two 200- and 400- [Formula: see text]-dia. electrodes, respectively, were applied. When higher level stimulation current of 100 and [Formula: see text] each were applied to the two 200- and 400- [Formula: see text]-dia. electrodes, respectively, maximum temperature increases of 1.2 °C in retina and 1 °C in deep brain region were found.

Simulation Study of an Ultrasound Retinal Prosthesis With a Novel Contact-Lens Array for Noninvasive Retinal Stimulation.

Millions of people around the world suffer from varying degrees of vision loss (including complete blindness) because of retinal degenerative diseases. Artificial retinal prosthesis, which is usually based on electrical neurostimulation, is the most advanced technology for different types of retinal degeneration. However, this technology involves placing a device into the eyeball, and such a highly invasive procedure is inevitably highly risk and expensive. Ultrasound has been demonstrated to be a promising technology for noninvasive neurostimulation, making it possible to stimulate the retina and induce action potentials similar to those elicited by light stimulation. However, the technology of ultrasound retinal stimulation still requires considerable developments before it could be applied clinically. This paper proposes a novel contact-lens array transducer for use in an ultrasound retinal prosthesis (USRP). The transducer was designed in the shape of a contact lens so as to facilitate acoustic coupling with the eye liquid. The key parameters of the ultrasound transducer were simulated, and results are presented that indicate the achievement of 2-D pattern generation and that the proposed contact-lens array is suitable for multiple-focus neurostimulation, and can be used in a USRP.

Acute Exposure to Pacific Ciguatoxin Reduces Electroencephalogram Activity and Disrupts Neurotransmitter Metabolic Pathways in Motor Cortex.

Ciguatera fish poisoning (CFP) is a common human food poisoning caused by consumption of ciguatoxin (CTX)-contaminated fish affecting over 50,000 people worldwide each year. CTXs are classified depending on their origin from the Pacific (P-CTXs), Indian Ocean (I-CTXs), and Caribbean (C-CTXs). P-CTX-1 is the most toxic CTX known and the major source of CFP causing an array of neurological symptoms. Neurological symptoms in some CFP patients last for several months or years; however, the underlying electrophysiological properties of acute exposure to CTXs remain unknown. Here, we used CTX purified from ciguatera fish sourced in the Pacific Ocean (P-CTX-1). Delta and theta electroencephalography (EEG) activity was reduced remarkably in 2 h and returned to normal in 6 h after a single exposure. However, second exposure to P-CTX-1 induced not only a further reduction in EEG activities but also a 2-week delay in returning to baseline EEG values. Ciguatoxicity was detected in the brain hours after the first and second exposure by mouse neuroblastoma assay. The spontaneous firing rate of single motor cortex neuron was reduced significantly measured by single-unit recording with high spatial resolution. Expression profile study of neurotransmitters using targeted profiling approach based on liquid chromatography-tandem mass spectrometry revealed an imbalance between excitatory and inhibitory neurotransmitters in the motor cortex. Our study provides a possible link between the brain oscillations and neurotransmitter release after acute exposure to P-CTX-1. Identification of EEG signatures and major metabolic pathways affected by P-CTX-1 provides new insight into potential biomarker development and therapeutic interventions.